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HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts

Heat shock protein 90 (HSP90) that is ubiquitously expressed in various tissues, is recognized to be a major molecular chaperone. We have previously reported that prostaglandin F(2α) (PGF(2α)), a potent bone remodeling mediator, stimulates the synthesis of interleukin-6 (IL-6) through p44/p42 mitoge...

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Autores principales: Fujita, Kazuhiko, Tokuda, Haruhiko, Kuroyanagi, Gen, Yamamoto, Naohiro, Kainuma, Shingo, Kawabata, Tetsu, Sakai, Go, Matsushima-Nishiwaki, Rie, Kozawa, Osamu, Otsuka, Takanobu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438147/
https://www.ncbi.nlm.nih.gov/pubmed/28542188
http://dx.doi.org/10.1371/journal.pone.0177878
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author Fujita, Kazuhiko
Tokuda, Haruhiko
Kuroyanagi, Gen
Yamamoto, Naohiro
Kainuma, Shingo
Kawabata, Tetsu
Sakai, Go
Matsushima-Nishiwaki, Rie
Kozawa, Osamu
Otsuka, Takanobu
author_facet Fujita, Kazuhiko
Tokuda, Haruhiko
Kuroyanagi, Gen
Yamamoto, Naohiro
Kainuma, Shingo
Kawabata, Tetsu
Sakai, Go
Matsushima-Nishiwaki, Rie
Kozawa, Osamu
Otsuka, Takanobu
author_sort Fujita, Kazuhiko
collection PubMed
description Heat shock protein 90 (HSP90) that is ubiquitously expressed in various tissues, is recognized to be a major molecular chaperone. We have previously reported that prostaglandin F(2α) (PGF(2α)), a potent bone remodeling mediator, stimulates the synthesis of interleukin-6 (IL-6) through p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells, and that Rho-kinase acts at a point upstream of p38 MAP kinase. In the present study, we investigated the involvement of HSP90 in the PGF(2α)-stimulated IL-6 synthesis and the underlying mechanism in MC3T3-E1 cells. Geldanamycin, an inhibitor of HSP90, significantly amplified both the PGF(2α)-stimulated IL-6 release and the mRNA expression levels. In addition, other HSP90 inhibitors, 17-allylamino-17demethoxy-geldanamycin (17-AAG) and 17-dimethylamino-ethylamino-17-demethoxy-geldanamycin (17-DMAG) and onalespib, enhanced the PGF(2α)-stimulated IL-6 release. Geldanamycin, 17-AAG and onalespib markedly strengthened the PGF(2α)-induced phosphorylation of p38 MAP kinase. Geldanamycin and 17-AAG did not affect the PGF(2α)-induced phosphorylation of p44/p42 MAP kinase and myosin phosphatase targeting subunit (MYPT-1), a substrate of Rho-kinase, and the protein levels of RhoA and Rho-kinase. In addition, HSP90-siRNA enhanced the PGF(2α)-induced phosphorylation of p38 MAP kinase. Furthermore, SB203580, an inhibitor of p38 MAP kinase, significantly suppressed the amplification by geldanamycin, 17-AAG or 17-DMAG of the PGF(2α)-stimulated IL-6 release. Our results strongly suggest that HSP90 negatively regulates the PGF(2α)-stimulated IL-6 synthesis in osteoblasts, and that the effect of HSP90 is exerted through regulating p38 MAP kinase activation.
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spelling pubmed-54381472017-05-27 HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts Fujita, Kazuhiko Tokuda, Haruhiko Kuroyanagi, Gen Yamamoto, Naohiro Kainuma, Shingo Kawabata, Tetsu Sakai, Go Matsushima-Nishiwaki, Rie Kozawa, Osamu Otsuka, Takanobu PLoS One Research Article Heat shock protein 90 (HSP90) that is ubiquitously expressed in various tissues, is recognized to be a major molecular chaperone. We have previously reported that prostaglandin F(2α) (PGF(2α)), a potent bone remodeling mediator, stimulates the synthesis of interleukin-6 (IL-6) through p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells, and that Rho-kinase acts at a point upstream of p38 MAP kinase. In the present study, we investigated the involvement of HSP90 in the PGF(2α)-stimulated IL-6 synthesis and the underlying mechanism in MC3T3-E1 cells. Geldanamycin, an inhibitor of HSP90, significantly amplified both the PGF(2α)-stimulated IL-6 release and the mRNA expression levels. In addition, other HSP90 inhibitors, 17-allylamino-17demethoxy-geldanamycin (17-AAG) and 17-dimethylamino-ethylamino-17-demethoxy-geldanamycin (17-DMAG) and onalespib, enhanced the PGF(2α)-stimulated IL-6 release. Geldanamycin, 17-AAG and onalespib markedly strengthened the PGF(2α)-induced phosphorylation of p38 MAP kinase. Geldanamycin and 17-AAG did not affect the PGF(2α)-induced phosphorylation of p44/p42 MAP kinase and myosin phosphatase targeting subunit (MYPT-1), a substrate of Rho-kinase, and the protein levels of RhoA and Rho-kinase. In addition, HSP90-siRNA enhanced the PGF(2α)-induced phosphorylation of p38 MAP kinase. Furthermore, SB203580, an inhibitor of p38 MAP kinase, significantly suppressed the amplification by geldanamycin, 17-AAG or 17-DMAG of the PGF(2α)-stimulated IL-6 release. Our results strongly suggest that HSP90 negatively regulates the PGF(2α)-stimulated IL-6 synthesis in osteoblasts, and that the effect of HSP90 is exerted through regulating p38 MAP kinase activation. Public Library of Science 2017-05-19 /pmc/articles/PMC5438147/ /pubmed/28542188 http://dx.doi.org/10.1371/journal.pone.0177878 Text en © 2017 Fujita et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Fujita, Kazuhiko
Tokuda, Haruhiko
Kuroyanagi, Gen
Yamamoto, Naohiro
Kainuma, Shingo
Kawabata, Tetsu
Sakai, Go
Matsushima-Nishiwaki, Rie
Kozawa, Osamu
Otsuka, Takanobu
HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts
title HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts
title_full HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts
title_fullStr HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts
title_full_unstemmed HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts
title_short HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts
title_sort hsp90 inhibitors potentiate pgf(2α)-induced il-6 synthesis via p38 map kinase in osteoblasts
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438147/
https://www.ncbi.nlm.nih.gov/pubmed/28542188
http://dx.doi.org/10.1371/journal.pone.0177878
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